TY - JOUR

T1 - Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in beta-Cells

AU - Dahlby, Tina

AU - Simon, Christian

AU - Backe, Marie Balslev

AU - Dahllof, Mattias Sailing

AU - Holson, Edward

AU - Wagner, Bridget K.

AU - Boni-Schnetzler, Marianne

AU - Marzec, Michal Tomasz

AU - Lundh, Morten

AU - Mandrup-Poulsen, Thomas

PY - 2020

Y1 - 2020

N2 - Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced beta-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the beta-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. beta-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF kappa B) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NF kappa B pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.

AB - Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced beta-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the beta-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. beta-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF kappa B) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NF kappa B pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.

KW - GLT

KW - histone deacetylases

KW - histone methyltransferase

KW - diabetes

KW - insulin secretion

KW - ER stress

KW - NF&#954

KW - B

KW - ENDOPLASMIC-RETICULUM STRESS

KW - LONG-TERM EXPOSURE

KW - HISTONE DEACETYLASES

KW - INSULIN-SECRETION

KW - PANCREATIC-ISLETS

KW - PROTEIN EZH2

KW - INS-1 CELLS

KW - FATTY-ACIDS

KW - INHIBITION

KW - EXPRESSION

U2 - 10.3390/ijms21218016

DO - 10.3390/ijms21218016

M3 - Journal article

C2 - 33137873

VL - 21

JO - International Journal of Molecular Sciences (Online)

JF - International Journal of Molecular Sciences (Online)

SN - 1661-6596

IS - 21

M1 - 8016

ER -